Download Product Monograph

PRODUCT MONOGRAPH
FOSRENOL®*
lanthanum carbonate hydrate
Chewable tablets
250mg, 500mg, 750mg, 1000mg lanthanum as lanthanum carbonate hydrate
Phosphate binder
Shire Pharma Canada ULC
2250 Alfred-Nobel Blvd, Suite 500
Saint-Laurent, Québec
H4S 2C9
Date of Preparation:
14 December 2012
Date of revision:
16 March 2016
*FOSRENOL is a registered trade-mark used under licence from Shire International Licensing
BV
Submission Control No: 189433
TABLE OF CONTENTS
PART I: HEALTH PROFESSIONAL INFORMATION .........................................................3
SUMMARY PRODUCT INFORMATION ........................................................................3
INDICATIONS AND CLINICAL USE ..............................................................................3
CONTRAINDICATIONS ...................................................................................................4
WARNINGS AND PRECAUTIONS ..................................................................................4
ADVERSE REACTIONS....................................................................................................6
DRUG INTERACTIONS ..................................................................................................10
DOSAGE AND ADMINISTRATION ..............................................................................12
OVERDOSAGE ................................................................................................................12
ACTION AND CLINICAL PHARMACOLOGY ............................................................13
STORAGE AND STABILITY ..........................................................................................15
DOSAGE FORMS, COMPOSITION AND PACKAGING .............................................15
PART II: SCIENTIFIC INFORMATION ...............................................................................17
PHARMACEUTICAL INFORMATION..........................................................................17
CLINICAL TRIALS ..........................................................................................................17
DETAILED PHARMACOLOGY .....................................................................................23
TOXICOLOGY .................................................................................................................23
REFERENCES ..................................................................................................................26
PART III: CONSUMER INFORMATION..............................................................................29
Page 2 of 31
FOSRENOL®
lanthanum carbonate hydrate
chewable tablets
PART I: HEALTH PROFESSIONAL INFORMATION
SUMMARY PRODUCT INFORMATION
Route of
Administration
Oral
Dosage Form /
Strength
Chewable tablets /
250, 500, 750 and
1000mg
Clinically Relevant Nonmedicinal
Ingredients
For a complete listing see Dosage Forms,
Composition and Packaging section.
INDICATIONS AND CLINICAL USE
FOSRENOL (lanthanum carbonate hydrate) is indicated as a phosphate binding agent in patients
with end stage renal disease on dialysis. The use of FOSRENOL in controlled clinical studies
beyond 2 years is limited. The risk versus benefit from administration beyond two years should
be carefully considered. (see Warnings and Precautions - Bone, Pharmacokinetics –
Distribution, and Clinical Trials – Bone Safety)
Geriatrics (>65 years of age)
Of the total number of patients in clinical studies of FOSRENOL, 32% (538) were ≥65 years of
age while 9.3% (159) were ≥75 years of age. No overall differences in safety or efficacy were
observed between patients ≥65 years of age and younger patients.
Pediatrics (<18 years of age)
The safety and efficacy of FOSRENOL have not been established in children. (see Warnings
and Precautions)
Page 3 of 31
CONTRAINDICATIONS
FOSRENOL (lanthanum carbonate hydrate) is contraindicated in patients with:
•
•
•
Bowel obstruction, ileus and fecal impaction
Hypophosphatemia
Hypersensitivity to lanthanum carbonate or to any ingredient in the formulation or
component of the container. For a complete listing, see the Dosage Forms, Composition
and Packaging section of the Product Monograph.
WARNINGS AND PRECAUTIONS
Carcinogenesis and Mutagenesis
See Toxicology – Mutagenicity and Carcinogenicity sections.
Gastrointestinal
Serious cases of gastrointestinal obstruction, ileus, subileus, gastrointestinal perforation and fecal
impaction have been reported in post-marketing follow-up of patients treated with FOSRENOL
(lanthanum carbonate hydrate), some requiring surgery or hospitalization.
Lanthanum is known to cause constipation (see Adverse Reactions – Clinical Trial Adverse
Drug Reactions). Exercise caution in all patients predisposed to gastrointestinal obstruction,
ileus, subileus and perforation; for example those with altered gastrointestinal anatomy (e.g.,
diverticular disease, peritonitis, history of gastrointestinal surgery, gastrointestinal cancer and
gastrointestinal ulceration) and hypomotility disorders (e.g., constipation, diabetic gastroparesis).
Some cases were reported in patients with no history of gastrointestinal disease.
The safety of FOSRENOL in patients with acute peptic ulcer, ulcerative colitis or Crohn’s
disease has not been established in clinical studies. Caution should be used in patients with these
conditions.
Advise patients to chew the tablet completely and not swallow whole (see Dosage and
Administration – Administration) to reduce the risk of serious adverse gastrointestinal events
such as those described above.
Hepatic/Biliary/Pancreatic
No studies have been done in patients with hepatic impairment. Although lanthanum is not
metabolized, it is excreted in the bile. Caution should be exercised in patients with hepatic
impairment or biliary obstruction, as elimination of absorbed lanthanum may be reduced.
Page 4 of 31
Bone
Tissue Deposition
Tissue deposition of lanthanum has been shown with FOSRENOL in animal and human studies.
The use of FOSRENOL in controlled clinical studies beyond 2 years is limited. The risk/benefit
from longer-term administration should be carefully considered. In bone biopsies of patients
treated with FOSRENOL for up to 4.5 years, rising levels of lanthanum were noted over time
(see Pharmacokinetics – Distribution; Warnings and Precautions – Long-term effects;
Clinical Trials – Bone Safety). There is no information on the re-distribution of lanthanum
eliminated from bone into other tissues upon termination of lanthanum carbonate therapy.
The effect of iron or aluminum chelation on serum lanthanum released from bone has not been
studied. Patients requiring chelation treatment who are taking FOSRENOL should be monitored
closely.
Long-term Effects
There were no differences in the rates of fracture in patients treated with FOSRENOL compared
to Standard Therapy∗ for up to 3 years. The duration of treatment exposure and time of
observation in the clinical program is too short to conclude that FOSRENOL does not adversely
affect bone quality or the risk for fracture or mortality beyond 3 years. (see Clinical Trials –
Bone Safety)
Special Populations
Pregnant Women
No adequate and well-controlled studies have been conducted in pregnant women. The effect of
FOSRENOL on the absorption of vitamins and other nutrients has not been studied in pregnant
women. FOSRENOL is not recommended for use during pregnancy. (see Toxicology –
Reproduction and Teratology)
Nursing Women
The excretion of lanthanum in milk has not been studied in animals. It is not known whether
lanthanum is excreted in human breast milk. Therefore, the use of FOSRENOL in women who
are breastfeeding is not recommended.
Geriatrics (>65 years of age)
Of the total number of patients in clinical studies of FOSRENOL, 32% (538) were ≥65 years of
age while 9.3% (159) were ≥75 years of age. No overall differences in safety or efficacy were
observed between patients ≥65 years of age and younger patients.
∗
Standard Therapy: Patients randomized to Standard Therapy continued to take their prescribed binder at the optimal dose
required to control their phosphate levels at ≤5.9mg/dL. Patients were allowed to switch phosphate binders throughout the study
and could also take a combination of binders in order to achieve optimal phosphate control.
Page 5 of 31
Pediatrics (<18 years of age)
The safety and efficacy of FOSRENOL have not been established in patients below the age of
18 years. While growth abnormalities were not identified in long-term animal studies, lanthanum
was deposited into developing bone including growth plate. The consequences of such
deposition in developing bone in pediatric patients are unknown. Therefore, the use of
FOSRENOL in pediatric patients is not recommended.
Monitoring and Laboratory Tests
Patients should adhere to recommended diets in order to control phosphate and fluid intake.
FOSRENOL is presented as a chewable tablet therefore avoiding the need to take additional
fluid. Serum phosphate levels should be monitored and the dose of FOSRENOL titrated every
2-3 weeks until an acceptable serum phosphate level is reached, with regular monitoring
thereafter.
ADVERSE REACTIONS
Adverse Drug Reaction Overview
Gastrointestinal symptoms including, but not limited to, nausea, vomiting, abdominal cramps
and diarrhea were observed in patients taking FOSRENOL. These symptoms were less frequent
when taking FOSRENOL with or immediately after food.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the
adverse reaction rates observed in the clinical trials may not reflect the
rates observed in practice and should not be compared to the rates in the
clinical trials of another drug. Adverse drug reaction information from
clinical trials is useful for identifying drug-related adverse events and for
approximating rates.
In three placebo-controlled studies in end stage renal disease (ESRD) patients, the most common
adverse events for FOSRENOL were gastrointestinal events such as nausea and vomiting, and
they generally abated over time with continued dosing. Adverse events that were more frequent
(≥5% difference) in the FOSRENOL group are presented in the following table.
Page 6 of 31
Table 1. Adverse Events that were More Common to FOSRENOL in PlaceboControlled, Double-blind Studies with Treatment Periods of 4-6 Weeks
FOSRENOL
%
(n=180)
Placebo
%
(n=95)
Dialysis Complication-NW
Dialysis Graft Occlusion
7.8
1.1
Gastrointestinal System Disorders
Nausea
10.6
5.3
Vomiting
9.4
4.2
Abdominal Pain
5.0
0.0
System Organ Class
Preferred Terminology (WHOART)
WHOART = World Health Organization Adverse Reactions Thesaurus,
NW = non-WHOART term developed by Sponsor for the clinical development program
The safety of FOSRENOL was studied in two long-term clinical trials that included
1215 patients treated with FOSRENOL and 944 with alternative therapy. Sixteen percent (16%)
of patients in these comparative, open-label studies discontinued in the FOSRENOL-treated
group due to adverse events. Gastrointestinal adverse events, such as nausea, diarrhea and
vomiting, were the most common type of event leading to discontinuation.
The number of withdrawals and the most common adverse events (≥5% in either treatment
group) in both the long-term (2-year), open-label, active-controlled, study of FOSRENOL vs.
alternative therapy (Study A) and the 6-month, comparative study of FOSRENOL vs. calcium
carbonate (Study B) are shown in Table 2 and Table 3, respectively. In Table 3, Study A events
have been adjusted for mean exposure differences between treatment groups (with a mean
exposure of 1.0 year on lanthanum and 1.4 years on alternative therapy). The adjustment for
mean exposure was achieved by multiplying the observed adverse event rates in the alternative
therapy group by 0.74.
Table 2. Number of Withdrawals/Phosphate Levels Achieved by Study Phase
Titration Phase
Maintenance
Phase
Study A*
Study B**
WITHDRAWALS
FOSRENOL
Alternative
FOSRENOL
Calcium Carbonate
Therapy
98/668 (14.67%)
38/670 (5.67%)
60/510 (11.96%)
41/257 (15.95%)
374/570 (65.61%)
311/632 (49.21%)
188/450 (41.78%)
103/207 (49.76%)
Page 7 of 31
Table 2. Number of Withdrawals/Phosphate Levels Achieved by Study Phase
Study A*
MEAN SERUM PHOSPHATE LEVEL ACHIEVED
Titration Phase 6.43mg/dL*
5.71mg/dL*
(2.06mmol/L)
(1.85mmol/L)
Maintenance
6.17mg/dL
6.05mg/dL
Phase
(1.97mmol/L)
(1.94mmol/L)
Study B**
1.87mmol/L **
1.66mmol/L **
1.73mmol/L
1.72mmol/L
*Study A: Patients in the FOSRENOL group were titrated over a six-week period starting from a dose of 750mg/day and then
maintained on doses up to 3000mg/day. The alternative therapy group started the titration phase at their optimal dose and were
subsequently maintained at their optimal dose with the allowance of switching/adding phosphate binders if they wished.
**Study B: Patients in the FOSRENOL group were titrated from 375mg/day up to their optimal dose and then maintained on
doses up to 3000mg/day. The calcium carbonate group started the titration phase at their optimal dose and were maintained on
doses up to 9000mg/day.
Table 3. Incidence of Treatment-Emergent Adverse Events that Occurred in ≥5% of Patients
(in Either Treatment Group) and in Both Comparative Studies A and B
Study A
%
(n=682)
37
27
Alternative*
Therapy
Adjusted Rates
(n=677)
29
22
25
24
3
5
24
22
24
21
13
5
10
6
21
21
4
6
17
18
5
3
16
15
5
4
4
18
14
6
6
8
8
6
5
7
0
9
7
6
6
20
FOSRENOL
Nausea
Vomiting
Dialysis graft
complication
Diarrhea
Headache
Dialysis graft
occlusion
Abdominal
pain
Hypotension
Constipation
Bronchitis
Rhinitis
Hypercalcemia
Study B
%
FOSRENOL
Calcium
Carbonate
(n=533)
16
18
(n=267)
13
11
*Alternative Therapy: Patients randomized to alternative therapy continued to take their prescribed binder at the optimal dose
required to control their phosphate levels at ≤5.9mg/dL. Patients were allowed to switch phosphate binders throughout the study
and could also take a combination of binders in order to achieve optimal phosphate control.
The dose range used in Study B was FOSRENOL 375mg–3000mg as elemental lanthanum and calcium carbonate
1500mg-9000mg elemental calcium.
Page 8 of 31
Less Common Clinical Trial Adverse Events
In clinical studies, the following other, less common (≥0.1% and <5%), adverse drug reactions
were reported:
Infections and Infestations: Gastroenteritis, laryngitis
Blood and Lymphatic System Disorders: Eosinophilia
Endocrine Disorders: Hyperparathyroidism
Metabolism and Nutrition Disorders:
Anorexia, appetite increased, hyperglycemia,
hyperphosphatemia, hypocalcemia, hypophosphatemia
Nervous System Disorders: Dizziness, taste alteration
Ear and Labyrinth Disorders: Vertigo
Gastrointestinal Disorders: Dry mouth, dyspepsia, eructation, esophagitis, flatulence,
gastrointestinal disorder NOS (not otherwise specified), indigestion, irritable bowel syndrome,
loose stools, stomatitis, tooth disorder
Skin and Subcutaneous Tissue Disorders: Alopecia, erythematous rash, itching, pruritus,
sweating increased
Musculoskeletal and Connective Tissue Disorders: Arthralgia, myalgia, osteoporosis
General Disorders and Administration Site Conditions: Asthenia, chest pain, fatigue,
malaise, pain, peripheral edema, thirst
Investigations: Alkaline phosphatase increased, blood aluminum increased, GGT increased,
hepatic transaminases increased, weight decrease
Although there have been a number of additional isolated events reported, none of these were
considered unexpected in this patient population.
In a comparative clinical study, patients on FOSRENOL had a lower incidence of hypercalcemic
episodes relative to patients on calcium-based phosphate binder (p<0.001).
Post-Market Adverse Drug Reactions
The following adverse reactions have been identified during post-approval use of FOSRENOL:
Gastrointestinal disorders: dyspepsia, ileus, intestinal obstruction, intestinal perforation,
subileus
General disorder: tooth injury
Skin and subcutaneous tissue disorders: allergic skin reactions (including pruritus, skin rashes
and urticaria)
Page 9 of 31
DRUG INTERACTIONS
Overview
Lanthanum carbonate hydrate is not a substrate for cytochrome P450 and does not significantly
inhibit the activities of the major human cytochrome P450 isoenzymes, CYP1A2, CYP2D6,
CYP3A4, CYP2C9 or CYP2C19 in vitro.
FOSRENOL does not alter gastric pH. Therefore, FOSRENOL drug interactions based on
altered gastric pH are not expected.
Drug-Drug Interactions
In Vitro Drug Interactions
Gastric Fluid: The potential for a physico-chemical interaction (precipitation) between
lanthanum and six commonly used medications (warfarin, digoxin, furosemide, phenytoin,
metoprolol and enalapril) was investigated in simulated gastric fluid. The results suggest that
precipitation in the stomach of insoluble complexes of these drugs with lanthanum is unlikely.
In Vivo Drug Interactions
No effects of lanthanum were found on the absorption of digoxin (0.5mg), metoprolol (100mg),
or warfarin (10mg) in healthy subjects co-administered lanthanum carbonate (three doses of
1000mg on the day prior to exposure and one dose of 1000mg on the day of co-administration).
Potential pharmacodynamic interactions between lanthanum and these drugs (e.g., bleeding time
or prothrombin time) were not evaluated. None of the drug interaction studies were done with the
maximum recommended therapeutic dose of lanthanum carbonate.
In healthy subjects, the absorption and pharmacokinetics of a single dose of 1000mg of
FOSRENOL was unaffected by co-administration of citrate.
FOSRENOL appears not to affect the intestinal absorption of fat soluble vitamins (A, D, E and
K), vitamin B12 or other nutrients (see Clinical Trials - Open-Label, Active-Controlled
Studies).
Co-administration of FOSRENOL (1000mg TID for 1 day) with calcitriol (2 x 0.5µg) to healthy
subjects did not significantly alter peak concentrations or overall extent of absorption of
calcitriol (1,25-dihydroxyvitamin D3).
Co-administration of FOSRENOL with quinolone antibiotics may reduce the extent of their
absorption as a result of complex formation. The bioavailability of oral ciprofloxacin was
decreased by approximately 50% when taken with FOSRENOL in a single dose study in healthy
volunteers. FOSRENOL should not be taken simultaneously with oral quinolone antibiotics.
The bioavailability of levothyroxine was decreased by approximately 40% when taken together
with FOSRENOL. FOSRENOL should not be taken simultaneously with thyroid hormones
Page 10 of 31
replacement therapy and closer monitoring of TSH levels is recommended in patients receiving
both medicinal products.
Other Possible Interactions
Interactions with drugs such as tetracycline and doxycycline are theoretically possible. If these
compounds are to be co-administered, it is recommended that they not be taken within 2 hours of
dosing with FOSRENOL.
There is a potential for FOSRENOL to interact with compounds which bind to cationic antacids
(e.g., aluminium-, magnesium-, or calcium-based). It is recommended that compounds known to
interact with antacids should not be taken within 2 hours of dosing with FOSRENOL
(e.g., chloroquine, hydroxychloroquine and ketoconazole).
No drug interaction studies assessed the effects of drugs on phosphate binding by lanthanum
carbonate.
The drug interactions profile of FOSRENOL is characterized by the potential of lanthanum to
bind to drugs with anionic functions (e.g., carboxyl, carbonyl and hydroxyl groups).
When administering any such medications where a reduction in the bioavailability of that
medication would have a clinically significant effect on safety or efficacy, the physician should
consider dosing that medicine apart from FOSRENOL or monitoring blood levels.
Drug-Herb Interactions
Interactions of FOSRENOL with herbs have not been established.
Drug-Laboratory Test Interactions
Abdominal X-rays of patients taking lanthanum carbonate may have a radio-opaque appearance
typical of an imaging agent.
Drug-Lifestyle Interactions
Interactions of FOSRENOL with lifestyle have not been established.
Page 11 of 31
DOSAGE AND ADMINISTRATION
Dosing Considerations
Serum phosphorus levels should be monitored as needed during titration until an optimal serum
phosphorus level is reached, and then on a regular basis thereafter.
Recommended Dose and Dosage Adjustment
The recommended initial daily dose of FOSRENOL (lanthanum carbonate hydrate) for adults is
750mg-1500mg. The dose should be titrated every 2-3 weeks to a level that achieves
maintenance of acceptable serum phosphorus levels. The daily dose should be divided and taken
with or immediately after meals. Patients should adhere to recommended diets in order to
control phosphate and fluid intake. FOSRENOL is presented as a chewable tablet, therefore
avoiding the need to take additional fluid.
In clinical studies in ESRD patients, FOSRENOL doses up to 4500mg were evaluated.
Most patients required a total daily dose between 1500 and 3000mg of FOSRENOL to reduce
serum phosphorus levels to less than 6.0mg/dL (1.92mmol/L). Doses were generally titrated in
increments of 750mg/day.
Missed Dose
A missed dose should be taken at the next scheduled dose with a meal. Taking a dose at a time
other than mealtime may lead to nausea and vomiting. Patients should not double-up the dose to
catch up.
Administration
Tablets should be chewed completely before swallowing. The tablets may be crushed as an
aid to chewing. Intact tablets should not be swallowed. Consider crushing tablets
completely for patients with poor dentition.
OVERDOSAGE
The highest daily dose of lanthanum carbonate administered to healthy adult subjects during a
Phase I study was 9000mg/day for 3 days. The symptoms associated with overdose are adverse
reactions such as headache, nausea and vomiting. Given the local activity of FOSRENOL in the
gut, and the excretion in feces of the majority of the dose, supportive therapy is recommended in
case of overdosage. Lanthanum carbonate was not acutely toxic in animals by the oral route
(see Toxicology – Single- and Repeat-Dose Toxicity).
Page 12 of 31
For management of a suspected drug overdose, contact your regional Poison Control Centre.
ACTION AND CLINICAL PHARMACOLOGY
Patients with ESRD can develop hyperphosphatemia as a result of phosphorus retention, which
may be associated with secondary hyperparathyroidism and elevated calcium phosphate product.
Treatment of hyperphosphatemia usually includes all of the following: reduction in dietary intake
of phosphate, removal of phosphate by dialysis and inhibition of intestinal phosphate absorption
with phosphate binders.
Mechanism of Action
FOSRENOL (lanthanum carbonate hydrate) acts in the lumen of the gut to bind dietary
phosphorus released from food during digestion. Lanthanum carbonate hydrate inhibits the
absorption of phosphorus by the formation of highly insoluble lanthanum phosphate complexes
that cannot easily pass through the wall of the gastrointestinal tract, and are excreted in the feces.
Pharmacodynamics
Lanthanum carbonate dissociates in the acid environment of the upper GI tract to release
lanthanum ions that bind dietary phosphate released from food during digestion. FOSRENOL
inhibits absorption of phosphate by forming highly insoluble lanthanum phosphate complexes,
consequently reducing both serum phosphate and calcium phosphate product.
In vitro studies have shown that in the physiologically relevant pH range of 3 to 5 in gastric
fluid, lanthanum binds approximately 97% of the available phosphate when lanthanum is present
in a two-fold molar excess to phosphate. In order to bind dietary phosphate efficiently,
lanthanum should be administered with or immediately after a meal.
Pharmacokinetics
Since the binding of dietary phosphorus occurs in the lumen of the stomach and upper small
intestine, plasma lanthanum concentrations are not predictive of lanthanum carbonate hydrate’s
efficacy.
Absorption
Following single or multiple dose oral administration of FOSRENOL to healthy subjects, the
concentration of lanthanum in plasma was very low, with oral bioavailability estimated to be
<0.002%.
In healthy subjects, plasma AUC and Cmax increased as a function of dose, but in a less than
proportional manner, after single oral doses of 250 to 1000mg lanthanum, consistent with
Page 13 of 31
dissolution-limited absorption. The apparent plasma elimination half-life in healthy subjects was
36 hours.
In renal dialysis patients dosed for 10 days with 1000mg lanthanum carbonate hydrate three
times daily, the mean (±sd) lanthanum Cmax was 1.06 (±1.04) ng/mL, and the mean AUClast was
31.1 (±40.5) ng·h/mL. During long-term administration (52 weeks) in renal dialysis patients,
the mean lanthanum concentration in plasma was approximately 0.6ng/mL. Regular blood level
monitoring in renal dialysis patients taking lanthanum carbonate hydrate (with increasing doses
within the therapeutic dose range) for up to 2 years showed minimal increase in plasma
lanthanum concentrations over this time period.
The effect of food on the bioavailability of FOSRENOL has not been evaluated, but the timing
of food intake relative to lanthanum administration (during and 30 minutes after food intake) has
a negligible effect on the systemic level of lanthanum.
Distribution
Lanthanum is present in the environment. Measurement of background levels in non-lanthanum
carbonate-treated ESRD patients on dialysis during Phase III clinical trials revealed
concentration of <0.05 to 0.90ng/mL in plasma, and <0.006 to 1.0µg/g in bone biopsy samples.
In vitro, lanthanum is highly bound (>99%) to human plasma proteins, including human serum
albumin, α1-acid glycoprotein, and transferrin. Binding to erythrocytes in vivo is negligible in
rats.
In long-term studies in mice, rats and dogs, absorbed lanthanum was widely distributed to
systemic tissues, predominantly bone, liver and the gastrointestinal tract, including the
mesenteric lymph nodes. Lanthanum concentrations in several tissues, including the
gastrointestinal tract, bone and liver, increased over time and were several orders of magnitude
higher than plasma concentrations. Changes in tissue lanthanum levels after withdrawal of
treatment varied between tissues. A relatively high proportion of lanthanum was retained in
tissues for longer than 6 months after cessation of dosing [median percent retained in bone
≤100% (rat) and ≤87% (dog) and in the liver ≤6% (rat) and ≤82% (dog)]. There is no evidence
from animal studies that lanthanum crosses the blood-brain barrier.
In 105 bone biopsies from patients treated with FOSRENOL for up to 4.5 years, rising levels of
lanthanum were noted over time. Steady-state bone concentrations were not reached during the
period studied (see Clinical Trials – Bone Safety). No clinical data are available on deposition
of lanthanum in other tissues in humans, including liver and gastrointestinal tract.
Metabolism
Lanthanum carbonate is not metabolized and is not a substrate of CYP450. In vitro metabolic
inhibition studies showed that lanthanum at concentrations of 10 and 40µg/mL does not have
relevant inhibitory effects on any of the CYP450 isoenzymes tested (1A2, C9, 2C19, 2D6 and
3A4).
Page 14 of 31
Excretion
Lanthanum was cleared from plasma following discontinuation of therapy with an elimination
half-life of 53 hours.
No information is available regarding the mass balance of lanthanum in humans after oral
administration. In healthy subjects, the majority of an orally administered dose was excreted in
the feces with only around 0.000031% of the oral dose excreted in the urine (representing <2%
of total plasma clearance).
Studies in chronic renal failure patients with hepatic impairment have not been conducted.
In patients with co-existing hepatic disorders at the time of entry into Phase III clinical studies,
there was no evidence of increased plasma exposure to lanthanum or worsening hepatic function
after treatment with FOSRENOL for periods up to 2 years.
Paired bone biopsies from 11 patients were collected after 12 months of lanthanum carbonate
treatment and 24-26 months after stopping lanthanum carbonate treatment. The mean bone
lanthanum concentration at the end of the treatment period was 2806µg/kg (range 530 to
5513µg/kg) and the mean concentration was 1903µg/kg (range 543 to 5683µg/kg) after
24-26 months off-treatment. This limited data demonstrated that lanthanum is slowly cleared
from bone. Its clearance showed considerable variability between individuals.
STORAGE AND STABILITY
Store between 15-25°C; excursions permitted up to 30°C. Protect from moisture.
Keep in a safe place out of the reach of children and pets.
DOSAGE FORMS, COMPOSITION AND PACKAGING
FOSRENOL is supplied as a chewable tablet in four dosage strengths for oral administration:
250mg tablets, 500mg tablets, 750mg tablets and 1000mg tablets. Each chewable tablet is white
to off-white, round, flat with a beveled edge, and embossed on one side with ‘S405’ and the
dosage strength corresponding to the content of the elemental lanthanum.
FOSRENOL 250mg chewable tablets are supplied in bottles of 90 and 400 tablets.
FOSRENOL 500mg chewable tablets are supplied in bottles of 45 tablets.
FOSRENOL 750mg chewable tablets are supplied in bottles of 15 tablets.
FOSRENOL 1000mg chewable tablets are supplied in bottles of 10 tablets.
Each chewable tablet of FOSRENOL (lanthanum carbonate hydrate) contains either 250, 500,
Page 15 of 31
750 or 1000mg of elemental lanthanum (as lanthanum carbonate hydrate) and the following
non-medicinal ingredients: colloidal silicon dioxide, dextrates (hydrated), and magnesium
stearate.
Page 16 of 31
PART II: SCIENTIFIC INFORMATION
PHARMACEUTICAL INFORMATION
Drug Substance
Proper name:
lanthanum carbonate hydrate
Chemical name:
lanthanum (III) carbonate hydrate
Molecular formula and molecular mass:
FOSRENOL contains lanthanum carbonate (2:3) hydrate with molecular formula
La2(CO3)3•qH2O (on average q=4 to 5 moles of water) and a molecular mass of 457.8
(anhydrous).
Physicochemical properties:
Lanthanum carbonate hydrate, a white to almost white powder, is a basic carbonate consisting
primarily of carbonate tetrahydrate, La2(CO3)3•4H2O, although other lanthanum hydrates may be
present with on average 4 to 5 moles of bound water. A macromolecular structure is formed from
the association of water molecules across the crystal lattice. The pKa values for its salt, carbonic
acid, are 10.33 and 6.35. Lanthanum carbonate is insoluble in organic solvents. Aqueous
solubility at a pH of 1.2 is between 5 and 10mg/mL, and is poor at alkaline pHs.
CLINICAL TRIALS
Study demographics and trial design
The effectiveness of FOSRENOL in reducing serum phosphorus in ESRD patients was
demonstrated in one short-term, placebo-controlled, double-blind dose-ranging study, two
placebo-controlled, randomized withdrawal studies and two long-term, active-controlled,
open-label studies in both hemodialysis and peritoneal dialysis (PD) patients.
Double-Blind, Placebo-Controlled Studies
One-hundred-forty-four patients with chronic renal failure undergoing hemodialysis and with
elevated phosphate levels were randomized to double-blind treatment at a fixed dose of
lanthanum carbonate of 225mg (n=27), 675mg (n=29), 1350mg (n=30) or 2250mg (n=26) or
placebo (n=32) in divided doses with meals. Fifty-five percent of subjects were male, 71% black,
25% white and 4% of other races. The mean age was 56 years and the duration of dialysis ranged
from 0.5 to 15.3 years.
Page 17 of 31
Fifty-four subjects [37 (33%) patients on FOSRENOL and 17 (53%) patients on placebo]
withdrew from the study after randomization. The reasons for discontinuation are described in
Table 4 below.
Table 4. Reasons for Discontinuation in Study LAM-204
FOSRENOL
(n=112 randomized)
Placebo
(n=32 randomized)
Total withdrawn
37 (33%)
17 (53%)
Adverse events, including death
10 (9%)
3 (9%)
Outside pre-specified safety
criteria*
19 (17%)
13 (41%)
Reason for Discontinuation
Administrative or other
8 (7%)
1 (3%)
2
2
* Including efficacy-related criteria such as PO4 >10mg/dL, PO4XCa >80mg /dL , and change in PTH >500pg/mL.
Steady-state effects were achieved after two weeks. The effect after six weeks of treatment is
shown in Figure 1.
Figure 1. Difference in Phosphate Reduction in the FOSRENOL and Placebo Group in a 6 Week,
Dose-ranging, Double-blind Study in ESRD Patients (with 95% Confidence Intervals)
Page 18 of 31
One-hundred-eighty-five patients with ESRD undergoing either hemodialysis (n=146) or
peritoneal dialysis (n=39) were enrolled in two placebo-controlled, randomized withdrawal
studies. Sixty-four percent of subjects were male, 28% black, 62% white and 10% of other races.
The mean age was 58.4 years and the duration of dialysis ranged from 0.2 to 21.4 years.
After a four- to six-week titration of lanthanum carbonate to achieve a goal phosphate level
between 4.2 and 5.6mg/dL in one study (doses up to 2250mg/day) or ≤5.9mg/dL in the second
study (doses up to 3000mg/day) and maintenance through 6 weeks, patients were randomized to
lanthanum or placebo.
Fifty (27%) of the subjects taking lanthanum in the titration phase withdrew (unplanned) from
the studies prior to randomization. The reasons for discontinuation were: adverse event including
1 death (16; 8.6%), outside pre-specified safety criteria (14; 7.6%), and protocol violation or
other (20; 10.8%).
During the placebo-controlled, randomized withdrawal phase (four weeks), the phosphorus
concentration rose in the placebo group by 1.9mg/dL in both studies relative to patients who
remained on lanthanum carbonate therapy.
Open-Label, Active-Controlled Studies
Two long-term, open-label studies were conducted, involving a total of 2159 patients with ESRD
undergoing hemodialysis. In Study LAM-301, 800 patients completed a washout period off
phosphate binders (Part 1) and were then randomized 2:1 to receive either FOSRENOL or
calcium carbonate. These patients were then dose-titrated to a target phosphate level of
≤1.8mmol/L over a five-week period (Part 2). On completion of titration, remaining patients
remained on their randomized phosphate binder and were followed for six months (Part 3). After
the six-month maintenance phase, all subjects who had been randomized were eligible to take
part in a longer-term extension on FOSRENOL only. The purpose of the extension was primarily
to assess safety and long-term tolerability of FOSRENOL.
Of the 767 subjects who entered the titration period (ITT population), 101 [FOSRENOL:
60 (11.8%); Calcium: 41 (16.0%)] withdrew before entering the maintenance phase of the study.
Two-hundred and ninety-one subjects [FOSRENOL: 188 (41.8%); Calcium: 103 (49.8%)]
withdrew during the maintenance phase (to end of Part 3). A total of 375 subjects (including
those who re-entered the study at the beginning of the extension) completed the six-month
randomized therapy and additional six-month open-label safety extension. The reasons for
discontinuation are shown in Table 5.
Page 19 of 31
Table 5. Reasons for Discontinuation in Study LAM-301
FOSRENOL
(n=533 randomized)
Calcium
(n=267 randomized)
271 (50.8%)
154 (57.7%)
Death
19 (3.6%)
11 (4.1%)
Adverse event
82 (15.4%)
47 (17.6%)
Serious adverse event
12 (2.3%)
4 (1.5%)
Protocol violation
24 (4.5%)
11 (4.1%)
Withdrew consent
43 (8.1%)
29 (10.9%)
Received kidney transplant
23 (4.3%)
16 (6.0%)
Lost to follow-up
5 (0.9%)
1 (0.4%)
64 (12.0%)
34 (12.7%)
Reason for Discontinuation
Total withdrawn
Other (including 1 missing)
At the end of the maintenance phase of the study, the mean phosphate level was 1.73mmol/L
(representing -0.74mmol/L from baseline) in the FOSRENOL group (doses up to 3000mg/day),
and 1.73mmol/L (representing -0.75mmol/L from baseline in the Calcium group (doses up to
9000mg/day) in patients who completed the maintenance period.
In Study LAM-307, 1359 patients were randomized to receive either FOSRENOL or Standard
Therapy*. Subjects completed a three-week washout period (Part 1) off all phosphate binders.
After a subsequent titration period of six weeks (Part 2), the patients were maintained on their
randomized treatment for 24 months (Part 3). A total of 682 patients were randomized to
FOSRENOL therapy, and 677 were randomized to Standard Therapy*.
Of the 1359 patients who entered the titration period, 842 (62%) withdrew prior to completion of
the two-year study. Of these, 486 (71.3%) were in the FOSRENOL group and 356 (52.6%) were
in the Standard Therapy∗group.
The reasons for discontinuation are shown in Table 6.
∗
Standard Therapy: Patients randomized to Standard Therapy continued to take their prescribed binder at the optimal dose
required to control their phosphate levels at ≤5.9mg/dL. Patients were allowed to switch phosphate binders throughout the
study and could also take a combination of binders in order to achieve optimal phosphate control.
Page 20 of 31
Table 6. Reasons for Discontinuation in Study LAM-307
FOSRENOL
(n=682 randomized)
Standard Therapy*
(n=677 randomized)
486 (71.3%)
356 (52.6%)
Death**
42 (6.2%)
96 (14.2%)
Adverse event
98 (14.4%)
29 (4.3%)
32 (4.7%)
22 (3.3%)
0
2 (0.3%)
Two CaXPO4 > 90mg /dL
14 (2.1%)
7 (1.0%)
Calcium > 11.5mg/dL
2 (0.3%)
1 (0.1%)
Increase PTH > 500pg/mL
5 (0.7%)
1 (0.1%)
Protocol violation
13 (1.9%)
5 (0.7%)
Withdrew consent
107 (15.7%)
34 (5.0%)
Patient received kidney transplant
55 (8.1%)
75 (11.1%)
Lost to follow-up
10 (1.5%)
12 (1.8%)
109 (16.0%)
73 (10.8%)
Reason for Discontinuation
Total withdrawn
Exceeded pre-specified safety
criteria:
Two PO4 > 10mg/dL
Two PO4 < 2.0mg/dL
2
Other
2
* Standard Therapy: Patients randomized to Standard Therapy continued to take their prescribed binder at the optimal
dose required to control their phosphate levels at ≤5.9mg/dL. Patients were allowed to switch phosphate binders
throughout the study and could also take a combination of binders in order to achieve optimal phosphate control.
** Represents End of Study entry as the investigator-determined reason for study withdrawal. There were patients who
died after study termination (13 FOSRENOL; 19 Standard Therapy). As a result, the total number of patients who died
whether during the study or within 30 days after the last dose of study drug was 178, who are not represented all on this
table.
Study LAM-307 was primarily a safety and tolerability study; phosphate control was a secondary
objective.
One-hundred and sixty-one patients entered a further 12-month extension of Study LAM-301,
taking FOSRENOL only, to a total of three years. Maintenance of phosphate reduction was
observed in patients treated with FOSRENOL for up to 3 years of which 62% received daily
doses of either 2250mg or 3000mg at Week 58. There were minimal dose changes throughout
the remainder of the study. Of the 90 patients who completed the third year of therapy, 49
(54.4%) had a phosphate level better than the target of 1.8mmol/L.
Page 21 of 31
In an open-label long-term 2-year extension study in 93 patients who had transitioned from other
studies, resulting in a total of up to 6 years treatment, maintenance of reduction in serum
phosphate level was observed. There was no evidence of adverse safety concerns after long-term
lanthanum carbonate treatment in any body system, including the hepatic system, bone and
central nervous system in the small number of patients remaining in their sixth year of treatment.
No effects of FOSRENOL on serum levels of 25-hydroxy and 1,25-dihydroxy vitamin D,
vitamin A, vitamin B12, vitamin E and vitamin K were observed in patients who were monitored
for 6 months.
Vital status was known for over 2000 patients, 97% of those participating in the clinical program
during and after receiving treatment. The adjusted yearly mortality rate (rate/years of
observation) for patients treated with FOSRENOL or alternative therapy was 6.6%.
Bone Safety
Lanthanum Deposition in Bone
In the comparative bone studies, a trend towards increasing bone lanthanum concentrations with
time in the Standard Therapy* group was observed from averaged data, the median rising 3-fold
from a baseline of 53µg/kg (wet weight) at 24 months. In patients treated with lanthanum
carbonate, the bone lanthanum concentrations increased during the first 12 months of lanthanum
carbonate treatment up to a median of 1328µg/kg (range 122-5513µg/kg). Median and range
concentrations at 18 and 24 months were similar to 12 months. The median at 54 months was
4246µg/kg (range 1673-9792µg/kg), a 3-fold increase from that at 12 months. Steady-state bone
concentrations were not reached during the period.
Bone Histology
Paired bone biopsies (at baseline and at one year) were collected from 63 patients randomized to
either FOSRENOL (n=33) or calcium carbonate (n=30) in one study. In a second randomized
study 99 patients had both a baseline and follow up biopsy after 1 or 2 years of treatment;
63 patients had bone biopsies at baseline and 1 year (FOSRENOL: n=31, Standard Therapy*:
n=32), and 52 patients had biopsies at baseline and 2 years (FOSRENOL: n=31, Standard
Therapy ∗: n=21). Histomorphometric analysis showed no differences in the development of
mineralization defects between the groups up to 2 years. However, long-term effects of
lanthanum on bone quality are unknown.
∗
Standard Therapy: Patients randomized to Standard Therapy continued to take their prescribed binder at the optimal dose
required to control their phosphate levels at ≤5.9mg/dL. Patients were allowed to switch phosphate binders throughout the
study and could also take a combination of binders in order to achieve optimal phosphate control.
Page 22 of 31
DETAILED PHARMACOLOGY
Preclinical
Pharmacodynamics
In vitro studies have shown that lanthanum binds phosphate in the physiologically relevant pH
range of 3 to 7. In normal rats, lanthanum carbonate (1000mg/kg p.o.) increased fecal excretion
of co-administered [32P]-phosphate and decreased urinary [32P]-phosphate excretion compared to
vehicle-treated controls, indicative of effective dietary phosphate binding. In partially
nephrectomised rats, lanthanum carbonate treatment (≥1000mg/kg) reduced, but not
significantly, the hyperphosphataemia and hyperparathyroidism associated with chronic renal
failure.
Pharmacokinetics
The absolute oral bioavailability of lanthanum (from lanthanum carbonate) was estimated from
oral and intravenous studies in rats to be 0.0007%. In rats and dogs, the mean recovery of
lanthanum after an oral dose was about 99% and 94% respectively and was essentially all from
feces. In bile-duct cannulated rats, biliary excretion of intravenous lanthanum (administered as
the soluble lanthanum chloride) was the predominant route of elimination.
Long-term studies in animals have shown deposition of lanthanum in tissues, mainly the
gastrointestinal tract, mesenteric lymph nodes, liver and bone (see also Action and Clinical
Pharmacology – Pharmacokinetics, Distribution). There is no evidence from animal studies
that lanthanum crosses the blood brain barrier.
TOXICOLOGY
Single- and Repeat-Dose Toxicity
In single-dose oral toxicity studies in mice and rats, lanthanum carbonate at doses up to
2000mg/kg resulted in no deaths and produced no overt signs of toxicity. Single-dose
intravenous toxicity studies in mice and rats were conducted using the soluble chloride salt of
lanthanum to ensure delivery of high systemic lanthanum doses. The maximum non-lethal
intravenous doses were 3.0mg/kg in the mouse and 6.25mg/kg in the rat. In both species, at
6.25mg/kg, histopathological changes in the liver included degeneration and necrosis of
hepatocytes, with hemorrhage and inflammation 2 days post-dose.
In repeat-dose oral toxicity studies in mice (for up to 99 weeks), rats (for up to 104 weeks), and
dogs (for up to 52 weeks), lanthanum carbonate was well tolerated at the maximum practicable
doses of 1500mg/kg/day in rodents and 2000mg/kg/day in dogs. In a 13-week oral toxicity study
in mice, lanthanum carbonate at doses up to 2000mg/kg/day was associated with a dosedependent accumulation of lanthanum particularly in the liver and femur. Epithelial hyperplasia
was observed in the gastric mucosa at doses of 500mg/kg/day or higher in rodents. No gastric
Page 23 of 31
pathology occurred in dogs, but there was a dose-related increase in lanthanum concentration in
the femur at the end of the 52-week treatment period.
Repeat-dose intravenous toxicity studies of 4 weeks duration with lanthanum chloride exposed
rats and dogs to peak plasma lanthanum concentrations that were approximately 1500 times
(rats, 0.3mg/kg/day) or 20 000 times (dogs, 1.0mg/kg/day) higher than in patients (assuming a
human Cmax of 1.06ng/mL after 1000mg of lanthanum carbonate hydrate TID). No adverse
effects occurred in rats. Chronic hepatitis was present in all male and female dogs given
1mg/kg/day.
Pre-clinical studies also found that chronically renal impaired rats given high doses of lanthanum
carbonate resulted in osteomalacia, and non-dietary phosphate supplements minimized this
effect.
Mutagenicity
Lanthanum carbonate tested negative for mutagenic activity in an in vitro Ames assay using
Salmonella typhimurium and Escherichia coli strains and an in vitro HGPRT gene mutation and
chromosomal aberration assays in Chinese Hamster Ovary (CHO) cells. Lanthanum carbonate
also tested negative in an in vivo mouse micronucleus assay at oral doses up to 2000mg/kg/day.
In addition, lanthanum chloride, administered intravenously, was shown to be non-clastogenic in
a bone marrow micronucleus test and in a liver unscheduled DNA synthesis assay in rats
at doses up to 0.1mg/kg/day, a dose that produced plasma lanthanum concentrations >2000 times
the peak human plasma concentration.
Carcinogenicity
Oral administration of lanthanum carbonate to rats for up to 104 weeks, at doses up to
1500mg/kg/day, revealed no evidence of carcinogenic potential. In mice, oral administration of
lanthanum carbonate for up to 99 weeks at a dose of 1500mg/kg/day was associated with an
increased incidence of gastric glandular adenomas. There were no treatment effects on the
incidences of malignant tumors.
Reproduction and Teratology
In pregnant rats, oral administration of lanthanum carbonate at doses up to 2000mg/kg/day
resulted in no evidence of harm to the fetus. There was an increased incidence of observations of
small pups in the group treated at 2000mg/kg/day. In pregnant rabbits, oral administration of
lanthanum carbonate at a dose of 1500mg/kg/day was associated with a reduction in maternal
body weight gain, food consumption, fecal production, increased pre- and post-implantation
losses, reduced fetal weights, and delayed fetal ossification.
Page 24 of 31
Oral administration of lanthanum carbonate to rats from implantation through lactation at
2000mg/kg/day caused delayed eye opening, reduction in body weight gain, and delayed sexual
development (preputial separation and vaginal opening) of the offspring.
Lanthanum carbonate at doses up to 2000mg/kg/day did not affect fertility or mating
performance of male or female rats.
Immunotoxicity
Specific immunotoxicity studies have not been performed.
Page 25 of 31
REFERENCES
1.
Al-Baaj F. Speake M, Hutchison AJ. Control of serum phosphate by oral lanthanum
carbonate in patients undergoing hemodialysis and continuous ambulatory peritoneal
dialysis in a short-term, placebo-controlled study. Nephrol Dial Transplat 2005;20:775-82.
2.
Autissier V, Damment SJ, Hernerson RA. Relative in vitro efficacy of the phosphate binders
lanthanum carbonate and sevelamer hydrochloride. J Pharma Sci 2007;96(10):2818-27.
3.
Behets GJ, Dams G, Vercauteren SR, Damment SJ, Bouillon R, De Broe ME, D’ Haese PC.
Does the phosphate binder lanthanum carbonate affect bone in rats with chronic renal
failure? J Am Soc Nephrol 2004; 15:2219-28.
4.
Damment SJ. Pharmacology of the phosphate binder, lanthanum carbonate. Ren Fail 2011;
33(2):217-25.
5.
Damment SJ, Pennick M. Systemic lanthanum is excreted in the bile of rats. Toxicol Lett
2007;171(1-2):69-77.
6.
Damment SJ, Pennick M. Clinical pharmacokinetics of the phosphate binder lanthanum
carbonate. Clin Pharmacokinet. 2008;47(9):553-63. Review.
7.
Damment SJP, Shen V. Assessment of effects of lanthanum carbonate with and without
phosphate supplementation on bone mineralization in uremic rats. Clin Nephrol
2005;67:127-37.
8.
David S, Cambi V. Haemodialysis and peritoneal dialysis. Medicine 1995;23:151-5.
9.
D’Haese PC, Spasovski GB, Sikole A, Hutchison A, Freemont TJ, Sulkova S, et al.
A multi-centre study on the effects of lanthanum carbonate (FOSRENOL) and calcium
carbonate on renal bone disease in dialysis patients. Kidney Int 2003;63(Suppl 85):S73-8.
10. Finn WF, Joy MS, Hladik G and Lanthanum Study group. Efficacy and safety of lanthanum
carbonate for reduction of serum phosphorus in patients with chronic renal failure receiving
hemodialysis. Clin Nephrol 2004;62:193-201.
11. Finn WF, SPD405-307 Lanthanum Study Group. Lanthanum carbonate versus standard
therapy for the treatment of hyperphosphatemia: safety and efficacy in chronic maintenance
hemodialysis patients. Clin Nephrol 2006;65:191-202.
12. Freemont T, Malluche HH. Utilization of bone histomorphometry in renal osteodystrophy:
demonstration of a new approach using data from a prospective study of lanthanum
carbonate. Clin Nephrol 2005;63:138-45.
Page 26 of 31
13. Ganesh SK, Stack AG, Levin NW, Hulbert-Shearon T, Port FK. Association of elevated
serum PO4, Ca X PO4 product, and parathyroid hormone with cardiac mortality risk in
chronic hemodialysis patients. J Am Soc Nephrol 2001;12:2131–8.
14. Graff L, Burnel D. A possible non-aluminum oral phosphate binder? A comparative study
on dietary phosphorus absorption. Res Commun Mol Path Pharmacol 1995;89:373-88.
15. Hanioka N, Jinno H, Sekita H, Toyo’oka T, Ando M, Kojima S, Takeda M. Metabolism of
calcium and phosphorus in rats after continuous oral administration of lanthanum. Jpn J
Toxicol Environ Health 1994;40:26-33.
16. How PP, Fischer JH, Arruda JA and Lau AH. Effect of lanthanum carbonate on the
absorption and oral bioavailability of ciprofloxacin. Clin J Am Soc Nephrol
2007;2:1235-40.
17. How PP, Mason DL, Arruda JA, Lau AH. Efficacy of chewed vs. crushed lanthanum on
phosphorous binding in healthy volunteers. Clin Nephrol 2010;73:370-3.
18. How PP, Anattiwong P, Mason Dl, Arruda JA and Lau AH. Phosphate-binding efficacy of
crushed vs. chewed lanthanum carbonate in hemodialysis patients. Hemodialysis
International 2010;15:95-9.
19. Hutchison AJ, Speake M, Al-Baaj F. Reducing high phosphate levels in patients with
chronic renal failure undergoing dialysis: a 4-week, dose-finding, open-label study with
lanthanum carbonate. Nephrol Dial Transplant 2004;19:1902-6.
20. Hutchison AJ, Maes B, Vanwalleghem J, Asmus G, Mohamed E, Schmieder R, et al.
Efficacy, tolerability, and safety of lanthanum carbonate in hyperphosphatemia: a 6-month,
randomized, comparative trial versus calcium carbonate. Nephron Clin Pract 2005;100:8-19.
21. Hutchison AJ, Maes B, Vanwalleghem J, Asmus G, Mohamed E, Schmieder R, et al.
Long-term efficacy and tolerability of lanthanum carbonate: results from a 3-year study.
Nephron Clin Pract 2006;102:c61-c71.
22. Hutchison AJ, Barnet ME, Krause R, Kwan JTC, Siami GA and Lanthanum Study Group.
Long-term efficacy and safety profile of lanthanum carbonate: Results for up to 6 years of
treatment. Nephron Clin Pract 2008;110:c15-c23.
23. Hutchison AJ, Laville M and Lanthanum Study Group. Switching to lanthanum carbonate
monotherapy provides effective phosphate control with a low tablet burden. Nephrol Dial
Transplant 2008;23:3677-864.
Page 27 of 31
24. Joy MS, Finn WF and Lanthanum Study Group. Randomized, double-blind,
placebo-controlled, dose-titration, Phase III study assessing the efficacy and tolerability of
lanthanum carbonate: a new phosphate binder for the treatment of hyperphosphatemia. Am J
Kidney Dis 2003;46:96-107.
25. Mehrotra R, Martin KJ, Fishbane S, Sprague SM, Zeig S and Anger M. Higher Strength
Lanthanum carbonate provides serum phosphorus control with a low tablet burden and is
preferred by patients and physicians: A multicenter study. Clin J Am Soc Nephrol
2008;3:1437-45.
26. Weitzman SP, Ginsburg KC and Carlson HE. Colesevelam hydrochloride and lanthanum
carbonate interfere with the absorption of levothyroxine. Thyroid 2009;19:77-9.
27. Zeiger E, Anderson B, Haworth S, Lawlor T, Mortelmans K. Salmonella mutagenicity
tests: V. Results from testing of 311 chemicals. Env and Mol Mut 1992;19:2-141.
Page 28 of 31
IMPORTANT: PLEASE READ
PART III: CONSUMER INFORMATION
®*
FOSRENOL
(lanthanum carbonate hydrate chewable tablets)
This leaflet is Part III of a three-part "Product Monograph"
published when FOSRENOL was approved for sale in Canada
and is designed specifically for Consumers. This leaflet is a
summary and will not tell you everything about FOSRENOL.
Contact your doctor or pharmacist if you have any questions
about the drug.
ABOUT THIS MEDICATION
What the medication is used for:
To reduce phosphorus levels in patients with end stage renal
disease who are on dialysis.
What it does:
FOSRENOL reduces the absorption of phosphate from food by
binding the phosphate in the gut.
When it should not be used:
You should not take FOSRENOL
• If you have a blockage in the intestine
• If you have severe constipation
• You have low blood phosphate levels
(hypophosphatemia)
• If you are allergic to any of the ingredients in
FOSRENOL (see “What the medicinal ingredient is” and
“What the important non medicinal ingredients are”).
What the medicinal ingredient is:
Lanthanum carbonate hydrate
What the important nonmedicinal ingredients are:
Colloidal silicon dioxide, dextrates (hydrated) and magnesium
stearate.
What dosage forms it comes in:
Chewable Tablets. Each chewable Tablet contains 250mg, 500mg,
750mg or 1000mg of lanthanum as lanthanum carbonate hydrate.
WARNINGS AND PRECAUTIONS
BEFORE you use FOSRENOL talk to your doctor or
pharmacist if:
• You have a history of blockage in the intestine, rupture of
the intestine wall, constipation, or diabetes
• You have had previous abdominal surgery
• You have suffered from peritonitis (inflammation of the
abdomen)
• You suffer from acute peptic ulcer, ulcerative colitis, or
Crohn’s disease
• You suffer from liver impairment or biliary obstructions
•
•
You are taking chelation therapy
You are pregnant, planning to get pregnant or nursing.
Tell your doctor that you are taking FOSRENOL before having
an X-ray of your stomach (abdomen), as this may affect the
results.
You should also be aware that:
• FOSRENOL is not for use in children under 18 years of
age
• Data from comparative studies lasting more than 2 years
is limited
• Bone lanthanum accumulation has been shown in
animals and humans.
INTERACTIONS WITH THIS MEDICATION
Drugs known to interact with antacids should not be taken within
2 hours before or after taking FOSRENOL (e.g., tetracycline,
doxycycline, chloroquine, hydroxychloroquine and ketoconazole).
It is not recommended that you take oral floxacin antibiotics
(including ciprofloxacin) simultaneously with FOSRENOL.
If you are taking thyroxine (for an underactive thyroid), do not
take it simultaneously with FOSRENOL; your doctor may want to
monitor blood levels of thyroid-stimulating hormone (TSH) more
closely.
Please inform your doctor or pharmacist if you are taking or have
recently taken any other medicines even those not prescribed.
PROPER USE OF THIS MEDICATION
Usual Dose:
Usual starting daily dose is between 750mg to 1500mg, to be
taken in divided doses and with or immediately after a meal. The
dose may be adjusted every 2 to 3 weeks. Most patients require a
daily dose between 1500mg and 3000mg.
The tablet should be chewed completely before swallowing.
Do not swallow tablets whole. If you cannot chew tablets, or if
you have poor dentition, you may crush tablets completely before
swallowing.
Overdose:
In case of drug overdose, contact a health care practitioner,
hospital emergency department or regional Poison Control
Centre immediately, even if there are no symptoms.
Page 29 of 31
IMPORTANT: PLEASE READ
Missed Dose:
If you miss a dose, then take the next scheduled dose at your
following meal. Taking a dose at a time other than mealtime may
lead to nausea and vomiting. Do not double dose to catch up.
SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN
AND WHAT TO DO ABOUT THEM
Symptom / Effect
SIDE EFFECTS AND WHAT TO DO ABOUT THEM
Only if
severe
The most common adverse events in clinical trials were
gastrointestinal such as nausea and vomiting.
You may also experience:
Dialysis graft complications, indigestion or heartburn, diarrhea or
soft stool, headache, constipation, respiratory infection, infection
of the throat, infection of the membrane of the nose, high blood
sugar levels, low or high blood phosphate levels, loss of appetite,
increased appetite, dizziness, strange tastes, trouble with digestive
system, gas, dry mouth, difficulty swallowing, sores in the mouth,
tooth disorder, tooth injury, losing some hair, itching, redness of
skin, rash, increased sweating, muscle and joint pain, fatigue,
malaise, pain, thirst, increased liver enzyme levels, increased blood
aluminium levels, and weight decrease.
To reduce side effects such as nausea, vomiting, abdominal cramps
and diarrhea, take FOSRENOL with or immediately after a meal.
SERIOUS SIDE EFFECTS, HOW OFTEN THEY HAPPEN
AND WHAT TO DO ABOUT THEM
Symptom / Effect
Talk with your
doctor or
pharmacist
Only if
severe
Very
common
Common
Uncommon
In all
cases
Allergic skin reaction
(including rashes; hives
and itching)
Hypotension (low
blood pressure)
√
Chest pain
√
Eosinophilia
(abnormal white blood
cell count)
Stop taking
drug and
call your
doctor or
pharmacist
√
In all
cases
Osteoporosis (bone
disease)
√
Peripheral edema
(swelling of limbs)
√
Stop taking
drug and
call your
doctor or
pharmacist
This is not a complete list of side effects. For any unexpected
effects while taking FOSRENOL, contact your doctor or
pharmacist.
HOW TO STORE IT
Store between 15-25°C; excursions permitted up to 30°C. Protect
from moisture.
Keep in a safe place out of the reach of children and pets.
REPORTING SUSPECTED SIDE EFFECTS
You can report any suspected adverse reactions associated with
the use of health products to the Canada Vigilance Program by
one of the following 3 ways:
-------------------------------------------------------------------------•
Report online at www.healthcanada.gc.ca/medeffect
•
Call toll-free at 1-866-234-2345
•
Complete a Canada Vigilance Reporting Form and:
- Fax toll-free to 1-866-678-6789, or
- Mail to: Canada Vigilance Program
Health Canada
Postal Locator 0701E
Ottawa, Ontario
K1A 0K9
Postage paid labels, Canada Vigilance Reporting Form
and the adverse reaction reporting guidelines are
available on the MedEffect™ Canada Web site at
www.healthcanada.gc.ca/medeffect.
√
Gastrointestinal
obstruction complete
(ileus) or incomplete
(subileus)
(abdominal bloating;
abdominal pain,
swelling or cramps,
constipation; vomiting)
Talk with your
doctor or
pharmacist
√
NOTE: Should you require information related to the management
of side effects, contact your health professional. The Canada
Vigilance Program does not provide medical advice.
MORE INFORMATION
Hyperparathyroidism
(enlarged parathyroid
glands)
√
Hypocalcemia (low
blood calcium levels)
√
If you want more information about FOSRENOL:
• Talk to your healthcare professional
• Find the full product monograph that is prepared for
healthcare professionals and includes this Patient
Medication Information by visiting the Health Canada
Page 30 of 31
IMPORTANT: PLEASE READ
website (http://hc-sc.gc.ca/index-eng.php) or by calling 1800-268-2772
This leaflet was prepared by Shire Pharma Canada ULC
Last revised: 16 March 2016
*FOSRENOL is a registered trade-mark used under licence from
Shire International Licensing BV.
© 2016 Shire Pharma Canada ULC. All rights reserved.
Page 31 of 31